Amyotrophic lateral sclerosis (hereinafter, ALS) is a motor neuron disease of poor prognosis, which develops at middle ages and thereafter and causes progressive paralysis of skeletal muscles. It is designated as a disease in the project for investigation and research into specific diseases sponsored by the Ministry of Health, Labor and Welfare of Japan. More than about 90% of cases of ALS are sporadic and the cause is unknown, whereas the remaining 10% are familial cases. To explain the causal factor in the latter cases, the gain-of-toxic function theory is likely wherein motor neuron death is caused by the cytotoxicity newly gained by mutated SOD1 (Cu/Zn superoxide dismutase) as a result of a point mutation of the SOD1 gene (1).
The only currently commercially available therapeutic drug for ALS is riluzole (Rilutek™, Aventis), a glutamate receptor antagonist possessing glutamate suppressing action (2).
In recent years, Yamanaka et al. succeeded in establishing iPS cells by transferring four genes into human skin fibroblasts (3, 4). Similarly, Thomson and his colleagues produced human iPS cells using Nanog and Lin28 in place of Klf4 and c-Myc (5, 6). Because the iPS cells thus obtained can be differentiated into cells of various tissues after being generated using cells derived from the patient to be treated, they are thought to enable reproduction of the pathologic condition in vitro. In fact, the above-described method was successfully applied to generate iPS cells from ALS patient and differentiate into neurons (7). Thus, using neurons induced from iPS cells derived from ALS patients, screening for a contributory therapeutic drug has been ongoing.
According to the IUPAC nomenclature system, sorafenib is a 1,3-diphenylurea derivative compound shown by 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyrimidine-2-carboxyamide.4-methylbenzenesulfonic acid (8), which is known as a multikinase inhibitor that inhibits kinases such as Raf1, blood vessel endothelial growth factor receptor (VEGFR)-2, -3, Flt3, platelet-derived growth factor receptor (PDGFR)-b, c-kit and the like, and is used as a therapeutic drug for progressive renal cell cancer (9). However, its effect on ALS is not known at all.